VALIDATION OF POLO-LIKE KINASE 1 AS A CANCER THERAPY TARGET

VALIDATION OF POLO-LIKE KINASE 1 AS A CANCER THERAPY TARGET

Left to right: Ray Erikson, Ming Lei and Xiaoqi Liu
A new study from the Erikson lab by Xiaoqi Liu and Ming Lei (just appearing in Molecular and Cellular Biology) offers important insight into the function of Polo-like kinase 1 and its role in cell regulation and carcinogenesis in mammalian cells.

Genetic and biochemical experiments with several different organisms have documented that the polo-like kinase (Plk) family serves as a vital regulator in many aspects of cell cycle progression. The mammalian family includes Plk1, an enzyme active in mitosis, and two other enzymes, Plk2 and Plk3, active early in the cell cycle.

A close correlation between mammalian Plk1 expression and carcinogenesis has been documented, and over-expression of Plk1 is observed in various human tumors. For example, elevated Plk1 expression is detected in human melanomas, and, furthermore, patients with moderate Plk1 expression survive significantly longer than those with high Plk1 levels. Similarly, non-small cell lung cancer patients whose tumors show moderate Plk1 expression survive significantly longer than those patients with high levels of Plk1 transcripts. Analysis of patients with head and neck squamous cell carcinomas, oropharyngeal carcinomas, ovarian and endometrial carcinomas, and esophageal and gastric cancer has revealed a close correlation between lower survival rates and higher Plk1 expression levels. Thus, it was proposed that Plk1 could serve as a novel diagnostic marker for several types of cancers, and that inhibition of Plk1 function may be an important approach for cancer therapy.

To document its functions in mammalian cells in more detail, the authors reported previously on the phenotype of cultured cancer cells after Plk1 depletion by the use of interfering RNA (RNAi). This approach revealed an essential role of Plk1 for cell proliferation and viability. Moreover, Plk1 depletion in cancer cells over an extended time induced apoptosis (cell death), as supported by the appearance of sub-genomic DNA, the activation of caspase 3, and the formation of fragmented nuclei.

Because inhibition of cell proliferation and activation of apoptosis are fundamental approaches to cancer therapy, it was of interest to test the effect of Plk1 depletion in normal human cells. In this study performed by Liu, a post-doctoral fellow in the lab, and Lei, a graduate student, Plk1 was depleted in several lines of normal human cells. In striking contrast to cancer cells, normal human cells were much less sensitive to Plk1 depletion; no apparent proliferation defect or cell cycle arrest was observed after Plk1 depletion. To probe for a possible mechanism for this result, p53 which is frequently mutated or absent in cancer cells, was depleted with RNAi in MCF10A, a normal human cell line, to render it more like a cancer cell. Depletion of p53 did not cause any immediate phenotypic changes and cells proliferated normally for several weeks.

However, upon subsequent severe depletion of Plk1, p53-depleted MCF10A cells were arrested prior to mitosis, but subsequently exhibited sub-genomic DNA, consistent with apoptosis events. Thus, under these conditions, otherwise normal p53-depleted MCF10A cells mimic cancer cells. Taken together, these data suggest new approaches for the study of Plk1 function in cell regulation and survival, and also emphasize the potential of Plk1 as a target in cancer therapy.